This document discusses the efficacy and risks of long-term NSAID therapy for rheumatic pain. It summarizes that all NSAIDs, both traditional and COX-2 selective, are associated with cardiovascular, renal, and gastrointestinal side effects. The risks of cardiovascular side effects are similar between diclofenac and coxibs. Low-dose ibuprofen and naproxen are associated with the lowest cardiovascular risk. When prescribing NSAIDs for long-term use, it is recommended to use the lowest effective dose for the shortest time, monitor for side effects, and consider co-prescribing a proton pump inhibitor to reduce gastrointestinal risks, especially in high-risk patients.

1. Efficacy & risk evaluation for long term therapy

2. Rheumatic pain
2

3. Symptoms
 Joint pain
 Joint swelling
 Morning stiffness
 Fatigue
 Weight loss
 Flu-like symptoms
3

4. Symptomatic Treatments
 Education/support
 Rest/relaxation
 Joint protection
 Physiotherapy
 Analgesics
 Anti-inflammatory drugs
 Steroids
 Joint injections
 Pain Management Clinics
4

5. Symptomatic Treatments
 Education/support
 Rest/relaxation
 Joint protection
 Physiotherapy
 Analgesics
 Anti-inflammatory drugs
 Steroids
 Joint injections
 Pain Management Clinics
5

6. Key questions regarding
NSAIDs*
 What are the benefits and risks from
NSAIDs?
 How do I reduce the GI risks?
 How do I reduce the CV risks?
 Are there specific safety concerns with
etoricoxib ?
 What does the prescribing data Iook like?
*Note by NSAIDs we mean traditional NSAIDs (e.g.
diclofenac, naproxen, ibuprofen); etodolac, meloxicam, or coxibs (e.g.
celecoxib, etoricoxib)

7. What are the benefits and risks of
NSAIDs?

8. NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008
Benefits and risks of
NSAIDs

9. Estimate of hospital-related
admissions due to NSAID adverse
reactions
Bandolier 2000;79:6–8
Event due to NSAID Estimated number of cases per
year per primary care group
(PCG)
Upper GI bleed 18
Acute renal failure 10
Congestive heart failure 22
Information based on an average PCG of 100,000 patients where 3,800
patients aged over 65 years take NSAIDs

10. NSAIDs: Renal risks
MHRA DSU. May 2009
Renal risk

11. How do I reduce the GI risks of
NSAIDs?

12.  No strong evidence to suggest NSAIDs have a
consistent benefit over paracetamol, although some
patients obtain greater symptom relief from NSAIDs
 Clinicians should consider offering paracetamol for
pain relief in addition to core treatment; regular dosing
may be required
 Paracetamol (and/or topical NSAIDs) should be
considered ahead of oral NSAIDs, COX-2 inhibitors or
opioids
Paracetamol>< NSAIDs
?
NICE Full Guideline 59: Osteoarthritis, Feb 2008
NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008

13. Using Paracetamol ?
Pincus T, et al. J Rheumatol 2000;27:1020–1027
Wolfe F, et al. Arthritis Rheumatol 2000;43:378–385

15. Risk of upper GI ulcer bleeding
Lanas A, et al. Gut 2006;55:1731–38
Hospital-based, case-control study
in Spain
2777 consecutive patients with
endoscopy-proved major upper GI
bleeding (peptic lesions) and 5532
matched controls
Use of NSAIDs increased risk
(RR 5.3;95%CI 4.5 to 6.2)
No increased risk for NSAIDs +
PPI (RR 0.9, 95%CI 0.7 to 1.3)
Rofecoxib increased the risk
(RR 2.1; 95%CI 1.1 to 4.0)
No increased risk with celecoxib
(RR 1.0; 95%CI 0.4 to 1.6)
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Control
Aceclofenac
Diclofenac
IbuprofenNaproxen
Lornoxicam
Ketoprofen
Indomethacin
MeloxicamKetorolac
CelecoxibRofecoxib
Paracetamol
AdjustedRR

16. NSAIDs: GI risks
 Ibuprofen offers the lowest GI risk; Coxibs are
associated with reduced GI risk relative to most
NSAIDs at equivalent doses
MeReC Extra 30. November 2007
 When offering treatment with an oral NSAID/coxib
inhibitor, the first choice should be either a
standard NSAID or a coxib (other than
etoricoxib 60mg). In either case, these should
be co-prescribed with a proton pump inhibitor
(PPI), choosing the one with the lowest
acquisition cost.
NICE. Osteoarthritis Guideline CG59. February 2008

17. How do I reduce the CV risks of NSAIDs?

18. Coxibs and cardiovascular
risk
MHRA. Safety of selective and non-selective NSAIDs
October 2006
 Coxibs are associated with an increased
thrombotic risk.
 Risk varies according to underlying patient risk
factors
 Population risk is about 3 additional events (mainly
MI) per 1000 patients per year compared with
placebo.
 Dose-related adverse effects may manifest early
and the risk may persist throughout treatment

19. Traditional NSAIDs and CV
risk
MHRA. Safety of selective and non-selective NSAIDs. October 2006
 Diclofenac 150mg daily has a similar excess thrombotic
risk to that of etoricoxib▼ and possibly other coxibs
 Naproxen 1000mg daily may be associated with a lower
risk of thrombotic events than coxibs. Although some risk
with naproxen cannot be entirely ruled out, epidemiological
evidence suggests that naproxen is not associated with an
excess risk of MI
 Ibuprofen may be associated with a small thrombotic risk
at high doses (e.g. 2400mg daily), whereas at low doses
(e.g. 1200mg daily) evidence does not suggest an
increased thrombotic risk in the short term

20. CV Issues With COX-2
Selective
and Traditional NSAIDs In placebo-controlled randomized trials, COX-2
selective NSAIDs ↑’ed the risk of thrombotic CV events
 Observational studies suggest ↑ CV risk for some
traditional NSAIDs
 CV risk of high-dose naproxen may be different:
 Meta-analysis of randomized trials: CV risk of high-
dose naproxen appears lower than COX-2 inhibitors
 2005-6 FDA and European regulatory agencies added
a warning of an increased thrombotic CV risk for all
NSAIDs (both COX-2 selective and traditional)
20
Kearney et al. BMJ. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092;
FDA. At: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed October 2006;
CHMP. At: http://www.emea.eu.int/pdfs/human/opiniongen/nsaids.pdf. Accessed October 2006.

21. Questions arising with COX-2
selective and traditional NSAID
therapies
These studies raise many questions:
1. Does greater COX-2 selectivity increase CV risk
vs. traditional NSAID?
2. Is high-dose naproxen, with its sustained
antiplatelet effect, different?
3. Would use of aspirin attenuate the increased risk
seen with NSAIDs?
Need large randomized trials comparing CV outcomes
between different NSAID agents
21

22. Primary Endpoint: Cumulative Incidence of Thrombotic
CV Events
22
Etoricoxib (320 events)
Diclofenac (323 events)
Months
No. of patients at risk*
Etoricoxib
Diclofenac
16,819
16,483
13,359 10,733 8277 6427 4024 805
81538326213790110,14212,800
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
6 12 18 24 30 36 420
Cumulativeincidence(%)with95%CI
Etoricoxib vs diclofenac
HR = 0.95
95% CI = (0.81-1.11)
*Per protocol population.

23. 23
Cumulative Incidence of Confirmed Upper GI
Events (Perforations, Ulcers, and Bleeds)*
POBs†
MonthsNo. of patients at risk
Etoricoxib
Diclofenac
17412
17289
13704 10972 8400 6509 4063 821
8203867630680271039613190
3.0
2.5
2.0
1.5
1.0
0.5
0
6 12 18 24 30 36 420
Cumulativeincidence(%)with95%CI
Etoricoxib vs
diclofenac
HR = 0.69
95% CI = (0.57-0.83)
*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.
Etoricoxib (176 events)
Diclofenac (246 events)
†No significant difference in perforations, obstructions, or major bleeds.

24. 24
“Our results show that patients with arthritis treated
with the COX-2 selective NSAID etoricoxib and those
given the traditional NSAID diclofenac have nearly
identical rates of thrombotic cardiovascular events.”
Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online) www.thelancet.com
Dr. Loren Laine is presenting preliminary GI subgroup
data at Am. Coll. Rheumatology in Wash DC today
For the lower risk upper GI clinical events with etoricoxib:
 Generally consistent benefit in ASA and PPI subgroups

25. 25

26. Etoricoxib and blood pressure
MHRA. DSU July 2008
 EMA review of etoricoxib
 Patients whose BP is persistently above 140/90 mmHg
and inadequately controlled must not receive etoricoxib
 High BP should be controlled before starting
treatment, and should be monitored for 2 weeks after the
start of treatment and regularly thereafter

27. Key messages
 All NSAIDS (both coxibs and traditional NSAIDs)
are associated with CV, renal and GI side effects
 Where NSAIDs are required, base prescribing on
the safety profiles of individual NSAIDs taking into
account individual patient risk factors
 Generally, prescribe NSAIDS at the lowest
effective dose and for the shortest period of time
necessary to control symptoms. Review
prescribing regularly.

28. Key messages
 The risks of CV side effects with diclofenac and
coxibs are similar
 Low-dose ibuprofen and naproxen are
associated with the lowest CV risk
 Consider co-prescribing a PPI with an
NSAID, especially to those at high risk of GI
side effects, and when used for long-periods of
time

29. Have an enjoyable learning